Visna is a slowly progressive disease of the central nervous system of sheep caused by persistent infection with an exogenous retrovirus. The brain lesion in visna is focal necrosis associated with large numbers of macrophages and lymphocytes. These lesions can be reproduced, and the slow disease accelerated, by sequential inoculation of the animal with antigenic mutant viruses which develop during the persistent infection. Recent studies have shown that the macrophage is an important target cell in this infection. Whereas antigenic drift may account for relapsing disease late in the infection, the macrophage may have a crucial role both in development of lesions and persistence of infection. This application centers around the infected macrophage. We propose to examine macrophage properties which may enhance infectivity of the virus and determine tissue tropism. These include the possible role of proteolytic enzymes, on which the virus may be dependent for maturation, and phagocytosis of infectious virus-antibody complexes which would perpetuate the infection. The ability of infected monocytes to respond to chemotactic stimuli will be studied because of the importance of these cells in disseminating virus in vivo. We will determine whether infected monocytes have alterations in surface receptors, enzyme secretion and phagocytocytic ability and study the effect of this infection on the development of humoral and cellular immune responses. These functions will be studied using monocyte dependent mitogen responses and primary in vitro immune responses to visna viral antigens. These are particularly relevant because American sheep with natural disease do not produce virus neutralizing antibody. Finally we will study the development of the brain lesion by direct inoculation and "induced invasion" of the neuropil with infected macrophages and also by addition of these cells to be infected cultures of fetal brain aggregates.